Various scientific articles and publications are referred to throughout the specification. These are incorporated by reference herein to describe the state of the art to which this invention pertains.
Sympathetic nervous system activation can result in increases in heart rate, blood pressure and cardiac contractility. Activities causing such a result can be physical exertion such as climbing, exercise, running or sexual intercourse. Likewise, symptoms such as sweating, tremor and palpitations can result from short-term stressful conditions which might be caused, for example, by "stage fright" because of public speaking, vocal or musical performance or phobias or panic attack. Control of heart rate, blood pressure and cardiac contractility during activities is particularly important for patients at risk due to coronary artery disease such as myocardial ischemic disorders. Severe attacks of chest pain, angina pectoris, occur when cardiac work and myocardial oxygen demand exceed the ability of the coronary arterial system to supply oxygen. The major determinants of myocardial oxygen consumption are heart rate, systolic tension (arterial pressure) and cardiac contractility. Any increase in any of these determinants in the presence of reduced coronary blood flow may induce angina. The higher the blood pressure and the faster the heart rate, the greater the unmet myocardial oxygen need. Rapid control of heart rate or blood pressure during such short term activities is particularly important for patients at risk due to coronary artery disease such as myocardial ischemic disorders. While long acting chronic, orally administrable beta blockers are available, the treatment of the conditions described often require drugs with fast onset of action and a relatively short duration of action which allows discontinuation of therapy in the event of severe side-effects. Such compounds and methods are described in the present invention.
Beta adrenergic blocking agents containing carboxylic ester groups are reported in the technical and patent literature. However, their corresponding carboxylic acids are generally taught to be inactive or only weakly active as beta blockers. Thus, a large group of ester containing compounds are reported as short-acting beta blocking agents when administered intravenously (J Med Chem. 1983, 1109-12; J Med Chem. 1982,1408; J Med Chem. 1982,1402; Life Sci. 1982,899; Pharm Res. 1995, 329; U.S. Pat. No. 4,387,103 issued on Jun. 7, 1983; U.S. Pat. No. 4,593,119, 1986 issued on Jun. 3, 1986; U.S. Pat. No. 4,692,446 issued on Sep. 8, 1987; U.S. Pat. No. 5,202,347 issued on Apr. 13, 1993) or topically as eye-drops for glaucoma (U.S. Pat. No. 4,455,317 issued on Jun. 19, 1984; U.S. Pat. No. 4,454,154 issued on Jun. 12, 1984; U.S. Pat. No. 4,578,403 issued on Mar. 25, 1986; U.S. Pat. No. 5,202,347 issued on Apr. 13, 1993; U.S. Pat. No. 4,829,086 issued on May 9, 1989), or by sublingual, buccal and intranasal administration (U.S. Pat. No. 5,536,749,1996). The basis for the short duration of action of these compounds was the rapid metabolism of the active esters to inactive or very weakly active carboxylic acids. (An "inactive beta blocker" is defined as a compound which is impractical to dose). The only examples of carboxylic acids with beta blocking activity are a compound with a carboxylic acid directly attached to an aromatic ring and one with a carboxylic acid conjugated with an aromatic ring (U.S. Pat. No. 3,961,071 issued on Jun. 1, 1976; and U.S. Pat. No. 3,888,993 issued on Jun. 10, 1975). No examples of ortho substituted phenyl aliphatic carboxylic acid beta blockers such as phenylpropionic acid containing compounds are known.
The drug esmolol (Physicians Desk Reference), shown below, is an intravenously infused beta blocking agent based on the "inactive metabolite" approach. It is marketed for acute treatment of cardiac disorders. This ester is rapidly metabolized in vivo to the corresponding carboxylic acid, which is reported to have an elimination half-life of 3.7 hours in man. During intravenous infusions, the acid metabolite accumulates to high concentrations in blood, but does not exhibit beta blocking activity. (Clin. Pharmacol. Ther. 34: 427-434, 1984). ##STR2##
The ethyl ester ACC-9369, shown above, was also reported to be rapidly converted in vivo to a metabolite, with little or no beta-blocking activity in dogs (J. E. Shaffer et al, Drug Development Research, 1: 221-232, 1986).
Glaucoma is a condition of the eye characterized by an increase in intraocular pressure. Untreated, the condition can eventually lead to irreversible retinal damage and blindness. Beta blockers have been the first line of therapy to reduce the IOP. After topical application of an eye drop, conjunctival and systemic absorption of drugs is typically an order of magnitude greater than their ocular absorption. In addition substantial systemic absorption of ophthalmic drugs takes place via the nasal mucosa. Systemic absorption of beta blocking agents may cause life threatening side-effects in patients with certain cardiac and pulmonary conditions. The ideal drug will only penetrate into the inner eye in order to reduce the intraocular pressure but will not produce any effects in the systemic circulation. A method for treating glaucoma with decreased systemic side effects, by topical administration of selectively metabolized potent beta-blocking agents has been described in U.S. Pat. No. 4,402,974 issued on Sep. 6, 1983; U.S. Pat. No. 4,455,317 issued on Jun. 19, 1984; U.S. Pat. No. 4,578,403 issued on Mar. 25, 1986; U.S. Pat. No. 4,454,154 issued on Jun. 12, 1984. When these compounds are absorbed systemically, the compounds are metabolized rapidly so that systemic beta blocking effects are relatively short acting. However, the drugs may cause an initial strong beta blocking effect until metabolism occurs.